Journal
CELL REPORTS
Volume 41, Issue 3, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2022.111489
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Funding
- Presidential Postdoc Fellowship
- Novartis Institutes for BioMedical Research (NIBR) Postdoc Office
- NIH [R01 AR062546, P50 AR070590, P30 AR075043]
- Taubman Medical Research Institute
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Through crystallography, biophysics, and mutational studies, this research demonstrates that IL-17A, IL-17F, and IL-17A/F induce IL-17RA dimerization, leading to the formation of a 2:2:2 hexameric signaling assembly. The formation of the IL-17 signalosome potentiates IL-17-induced IL-36 gamma and CXCL1 mRNA expression in human keratinocytes compared to a dimerization-defective IL-17RA variant.
Signaling through innate immune receptors such as the Toll-like receptor (TLR)/interleukin-1 receptor (IL-1R) superfamily proceeds via the assembly of large membrane-proximal complexes or ''signalosomes.'' Although structurally distinct, the IL-17 receptor family triggers cellular responses that are typical of innate immune receptors. The IL-17RA receptor subunit is shared by several members of the IL-17 family. Using a combination of crystallographic, biophysical, and mutational studies, we show that IL-17A, IL-17F, and IL-17A/F induce IL-17RA dimerization. X-ray analysis of the heteromeric IL-17A complex with the extracellular domains of the IL-17RA and IL-17RC receptors reveals that cytokine-induced IL-17RA dimerization leads to the formation of a 2:2:2 hexameric signaling assembly. Furthermore, we demonstrate that the formation of the IL-17 signalosome potentiates IL-17-induced IL-36 gamma and CXCL1 mRNA expression in human keratinocytes, compared with a dimerization-defective IL-17RA variant.
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